MSA is a relentlessly progressive and fatal disease characterized by parkinsonism or cerebellar dysfunction and autonomic failure. This PPG, founded by the late Dr. Cliff Shults, is devoted to studies on the pathogenesis and management of MSA. The success and insights gleaned from the last 5 years has enabled us to consolidate, modify, and improve the competing renewal proposal into 3 tightly integrated Cores and 4 Projects with important and achievable endpoints. We have achieved our original goal of recruiting 175 patients with MSA. Preliminary data has led us to modify Project 1 from an epidemiologic study (which has been completed) to an ongoing prospective study that will identify predictors of outcome. Specifically, Project 1 (Oilman) will test the hypothesis that clinical phenotype at onset and autonomic symptoms are predictive of clinical course. This MSA patient cohort will be expanded to 275 patients, by adding 100 additional patients with milder and earlier MSA. Project 1 will additionally study adrenergic innervation of the heart ([llCjhydroxyephedrine labeling), using high resolution PET scanning of the heart. Project 2 (Benarroch) will undertake a morphometric immunohistochemical study on key neuronal groups in hypothalamus. Dr. Masliah will continue his focus on the molecular pathogenesis of MSA. He has developed a transgenic mouse model that mimics human MSA, with glial-cytoplasmic inclusion (GCI) and neuronal loss. He continues his studies to increase or reverse GCI and behavioral deficits. Dr. Benarroch will apply his morphometric analysis of relevant nuclear groups and GCI to this mouse model. Dr. Low will continue his prospective study of laboratory autonomic indicators of a more progressive course. He will additionally undertake a double-blind placebo controlled study to evaluate a novel approach to improving orthostatic hypotension without worsening supine hypertension. A key large pilot study will focus on a treatment trial of Rifampicin, which could potentially halt progression or reverse the pathogenesis of MSA, based on results from Project 3. The study will be conjointly carried out by Projects 1 and 4 and supported by Core A. These projects will continue to be supported by 3 cores.